The thymus is considered by some to be an endocrine organ producing hormones that regulate the development and function of the immune system. We have recently isolated two peptides from rat thymus, designated prothymosin Alpha and parathymosin Alpha, respectively, and will study their structure, the mechanism of their biosynthesis and its regulation and their effects on cell-mediated immunity. Biochemical studies will be designed to determine (1) the amino acid sequences of these peptides, (2) the mechanism of their biosynthesis and degradation, (3) their distribution in tissues and body fluids using RIA's specific for epitopes at the NH2- and COOH-termini to distinguish between the intact peptides and NH2-terminal fragments such as thymosin Alpha1, (4) changes in the concentration of either polypeptide in response to modulation of immune function resulting from administration of the other peptide, and (5) the identification of other lymphokines whose release is affected by these peptides. The goal of the immunological studies will be to determine how these thymic peptides interact to promote and regulate cell-mediated immunity (CMI). Prothymosin Alpha has been found to stimulate CMI; parathymosin Alpha has been found to inhibit (or regulate) the CMI-promoting activity of prothymosin Alpha. Together, they represent a potential thymic hormonal system for the control of CMI. The studies will be carried out in inbred mice strains: (a) resistant to infection with Candida albicans and Mycobacterium bovis BCG, high responders in the in vivo release of the lymphokines and migration inhibitory factor (MIF) and interferon-Gamma (IFN-Gamma), and strong reactors in delayed cutaneous hypersensitivity; and (b) susceptible to infection with C. albicans and M. bovis BCG, low responders in the in vivo release of MIF and IFN-Gamma, and poor or non-reactors in delayed cutaneous hypersensitivity. Experiments will be set up to determine (a) the mechanism whereby macrophages are stimulated by administration of prothymosin Alpha, (b) what class of lymphocytes, if any, is activated, and (c) what soluble mediators, if any, are released by the activated lymphocytes that result in activated macrophages. Similar experiments will be initiated to determine the mechanism by which parathymosin Alpha modulates the action of prothymosin Alpha. Present evidence suggests that one mechanism for homeostasis of cell-mediated immunity may lie in the interrelationship of prothymosin Alpha versus parathymosin Alpha.